This is a U.S. National Phase Application Under 35 USC 371 and applicant herewith claims the benefit of priority of PCT/JP00/00512 filed Jan. 31, 2000, in the Japanese Patent Office and Application No. 11-042695 filed in Japan on Feb. 22, 1999 each of whose contents are incorporated by reference.
The present invention relates to maltoligosaccharide derivatives having a specific molecular structure and their uses. More particularly, it relates to an xcex1-amylase inhibitor and the pharmaceuticals useful for the prophylaxis and treatment of hyperglycemia, for example, diabetes and their complications, which contain said derivatives as an active ingredient.
Carbohydrates ingested by mammals are digested (hydrolyzed) to some extent by salivary xcex1-amylase in the oral cavity and stomach, and then digested thoroughly by pancreatic xcex1-amylase in the duodenum and jejunum to become oligosaccharides or disaccharides. Then they are further hydrolyzed by a glucoside-hydrolaze such as glucoamylase and maltase to finally become a monosaccharide such as glucose which is absorbed from the fimbriae on the intestinal membranes. After ingestion of carbohydrates, there takes place a primary increase in blood glucose level, or so-called hyperglycemic symptom, due to the absorption of glucose, but this abnormal phenomenon is usually remedied in due course as the blood glucose level is brought back to a normal range and controlled to stay therein by the homeostasis maintaining system in the living body.
However, if a person suffers an alimentary hyperglycemic symptom for a long time or has abnormality in carbohydrate metabolism, such as an abnormal rise of blood glucose level, he or she is liable to a disease called hyperglycemia, which leads to obesity or diabetes. Obesity is caused as the hyperglycemic condition resulting from overeating incites much secretion of insulin to promote fat synthesis and to decrease lipolysis, inducing accumulation of fat in the body. On the other hand, diabetes is caused as the promoted secretion of insulin by the hyperglycemic condition resulting from overeating invites a reduction of sensitivity of the insulin receptors or fatigue of the xcex2 cells of the pancreatic Langerhans islet. It is known that obesity and diabetes tend to provoke many serious complications such as hyperlipidemia, hypertension, arteriosclerosis, autonomic imbalance, and cataract.
As a potent therapeutic agent for such hyperglycemia, certain digestive enzyme inhibitors, for example, xe2x80x9cBasenxe2x80x9d containing Voglibose (produced by Takeda Chemical Industries Co., Ltd.) and xe2x80x9cGlucobayxe2x80x9d containing Acarbose (produced by Bayer Chemical Corp.), are clinically used. Both of these compounds, however, have the disadvantage of inciting such side effects as causing abdominal distention, meteorism, increase of flatus, loose passage, diarrhea, abdominal pain, etc., because of their strong inhibitory action against glucosidase. Also, the maltoligosaccharide derivatives which the present inventors had previously proposed (JP-A-9-278789) are not necessarily satisfactory in certain respects, such as strength of their amylase inhibitory activity.
The present invention is intended to provide a chemical substance which is free of said defects of the conventional therapeutic and prophylactic agents for hyperglycemia and capable of strongly inhibiting human xcex1-amylase to work effectively for the prophylaxis and treatment of hyperglycemia, for example diabetes and the diseases induced thereby, and an xcex1-amylase inhibitor and prophylactic and therapeutic agents for hyperglycemia containing said substance as an active ingredient.
The inventors extensively studied for attaining the above object, and found that the maltoligosaccharide derivatives produced by converting the reduced terminal glucose of oligosaccharides into hexahydro-1H-azepine-3R, 4R, 5R, 6S-tetrol and also converting the 6-position of the 3rd glucose residue (as counted from the hexahydro-1H-azepine-3R, 4R, 5R, 6S-tetrol) into a hydrophobic group, and their hydrates or their physiologically acceptable salts strongly inhibit xcex1-amylase derived from human pancreatic juice (hereinafter referred to as HPA) and xcex1-amylase derived from human salivary gland (hereinafter referred to as HSA) and also act to suppress or retard digestion and absorption of glucose, and that it is possible to overcome the said defects of the prior art by using these compounds as an active ingredient of the therapeutic and prophylactic agents for hyperglycemia. The present invention has been attained on the basis of the above finding.
According to the present invention, there are provided the maltoligosaccharide derivatives represented by the following general formula (1): 
(wherein n is an integer of 0 to 3, and X is a hydrogen atom or a hydrophobic group) or their hydrates or physiologically acceptable salts; an xcex1-amylase inhibitor containing one of said maltoligosaccharide derivatives of the formula (1) or their hydrates or physiologically acceptable salts as an active ingredient; and a prophylactic or therapeutic agent for hyperglycemia containing one of said maltoligosaccharide derivatives of the formula (1) or their hydrates or physiologically acceptable salts as an active ingredient. The present invention is explained in detail.
The maltoligosaccharide derivatives according to the present invention (hereinafter referred to as the present derivatives) are those which are represented by the general formula (1) as mentioned above wherein n is an integer of 0 to 3 and X is a hydrogen atom or a hydrophoblic group. The present derivatives include their hydrates and physiologically acceptable salts. The hydrophobic group represented by X can be, for instance, a halogen atom such as fluorine, chlorine, b romine and iodine atom, a substituted or non-substituted alkyloxy group, a substituted or non-substituted alkylthio group, a substituted or non-substituted alkylsulfonyl group, a substituted or non-substituted alkylcarbamoyl, or azido group.
In use of the present derivatives for producing an xcex1-amylase inhibitor or a prophylactic or therapeutic agent for hyperglycemia, it is desirable, for the reasons stated below, that in the formula (1) n is 0 to 3, especially 0 or 1, and X is a hydrogen atom or a halogen atom, especially a hydrogen atom.
The present derivatives can be synthesized efficiently from, for instance, 63-modified maltoligosaccharides represented by the general formula (2): 
(wherein n is an integer of 0 to 3, and X is a hydrogen atom or a hydrophobic group). In the formula (2), n is an integer of 0 to 3, and X is a hydrogen atom or a hydrophobic group. The hydrophobic group can be, for instance, a halogen atom such as fluorine, chlorine, bromine and iodine atom, a substituted or non-substituted alkyloxy group, a substituted or non-substituted alkylthio group, a substituted or non-substituted alkylsulfonyl group, a substituted or non-substituted alkylcarbamoyl, or azido group. Said 63-modified maltoligosaccharides can be synthesized, for instance, by a method described in Carbohydrate Research, Vol. 307, pp. 69-76, 1998.
A 63-modified maltologosaccharide synthesized by the above method is reacted with, for instance, p-toluenesulfonyl chloride in pyridine, and if necessary 61-tosyl-63-modified maltoligosaccharide are separated by a conventional method and reacted with sodium azide in N,N-dimethylformamide (DMF) to give 61-azido-63-modified maltoligosaccharides. These 61-azido-63-modified maltoligosaccharides are separated from each other by a known method, and the latter is reduced by introducing hydrogen gas in the presence of palladium carbon to produce the present derivative represented by the formula (1).
The thus obtained present derivative can be purified by a conventional method, for example, precipitation using a pertinent organic solvent or column chromatography using an ion exchange resin, aminopropyl silica gel, silica gel, active carbon, etc.
The present derivatives represented by the formula (1), obtained in the manner described above, have a strong inhibitory acitivity against HPA and HSA as explained below. In comparison with the maltoligosaccharide derivatives of the formula (1) wherein X is a non-modified group (OH group), which the present inventors had previously proposed (JP-A-9-278789), the present derivatives in which a hydrogen atom or a hydrophobic group has been introduced to the X position are remarkably enhanced in amylase inhibitory activity. Also, the above-mentioned prior art maltoligosaccharide derivatives or their hydrates or physiologically acceptable salts, although having an action to suppress the blood glucose level after meal, are susceptible to decomposition in the intestinal tracts and may therefore be greatly weakened in their activity. In contrast, the present derivatives, since X is modified, are enhanced in their amylase inhibitory activity and not easily decomposed in the intestinal tracts, so that their activity keeps long in the intestinal tracts. Consequently, a high blood glucose level suppressing effect after meal can be obtained by a small dosage of the compound. In view of affinity with amylase, the present derivatives represented by the formula (1) are preferably those in which in the formula (1) n is 0 to 3, especially 0 or 1, and X is a hydrogen atom or a halogen atom, especially a hydrogen atom.
As explained above, the present derivatives have a strong inhibitory activity against xcex1-amylase, so that a potent xcex1-amylase inhibitor can be obtained by using such derivatives as an active ingredient. Further, the present derivatives having such an inhibitory activity also depress carbohydrate metabolism of animals, so that they can check the increase in blood glucose level and are therefore useful as a prophylactic or therapeutic agent for hyperglycemia, for example, diabetes, adiposity and the diseases caused thereby, such as hyperlipidemia, fatty liver, autonomic imbalance, arteriosclerosis, cataract, etc. The present derivatives are especially useful for the prophylaxis and treatment of diabetes.
Nontoxic salts obtained by reacting the present derivatives with a pharmacologically acceptable acid or base in the usual method can also be used for the preparation of the xcex1-amylase inhibitor or prophylactic or therapeutic agents for hyperglycemia according to the present invention. The acids usable for the above reaction include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid and nitric acid, and organic acids such as acetic acid, malic acid, citric acid, ascorbic acid, mandelic acid and methanesulfonic acid. The bases include sodium hydroxide, potassium hydroxide, ammonium hydroxide, calcium hydroxide, etc.
The xcex1-amylase inhibitor and the prophylactic or therapeutic agent for hyperglycemia according to the present invention can be obtained by using the present derivatives either singly or as a combination of two or more of them as an active ingredient. Also, the xcex1-amylase inhibitor and the prophylactic or therapeutic agent for hyperglycemia according to the present invention may comprise the present derivative alone or may further contain other compounding agent(s) such as excipient, lubricant, diluent, stabilizer, pH adjuster, antiseptic, sweetener, aromatic, flavor, colorant, preservative, emulsifier, thickening agent, and base materials to provide the preparations of various dosage forms such as tablet, powder, granule, capsule, syrup, sappository, injection and drops. Conventional methods can be used for making these preparations. As excipient, ordinarily used potato starch, lactose, crystal cellulose, mannitol and the like may be used. As lubricant, magnesium stearate, talc, hard oil and the like may be used. As sweetener, aromatic and flavor, there may be used common salt, saccharin, orange oil, citric acid, menthol, malic acid, etc.
The dosage of the xcex1-amylase inhibitor, prophylatic or thermapeutic agent for hyperglycemia, and prophylatic or thermapeutic agent for diabetes according to the present invention is variable depending on the route of administration, condition of the disease, patient""s age and body weight, and other factors, but usually it is selected from within the range of 10 to 3,000 mg, preferably 100 to 600 mg (as the present derivative) per day for the adult. The route of administration may be either oral or parenteral, but oral administration is advantageous. The present derivative may be contained, either alone or in combination with other compounding agent(s) such as mentioned above, in foods such as coffee, soft drinks, fruit juice, jam and biscuits to provide health foods having an xcex1-amylase inhibitory effect.